ω-3 PUFAs ameliorate liver fibrosis and inhibit hepatic stellate cells proliferation and activation by promoting YAP/TAZ degradation.

Kun Zhang,Tao Han,Lina Zheng,Xiaohui Han,Yanan Chang,Hongmei Cui,Yawei Han,Zhemin Shi,Wei Hong,Zhimei Hu,Qingbin Yao

doi:10.1038/srep30029

Abstract

Elevated levels of the transcriptional regulators Yes-associated protein (YAP) and transcriptional coactivators with PDZ-binding motif (TAZ), key effectors of the Hippo pathway, have been shown to play essential roles in controlling liver cell fate and the activation of hepatic stellate cells (HSCs). The dietary intake of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) has been positively associated with a number of health benefits including prevention and reduction of cardiovascular diseases, inflammation and cancers. However, little is known about the impact of ω-3 PUFAs on liver fibrosis. In this study, we used CCl4-induced liver fibrosis mouse model and found that YAP/TAZ is over-expressed in the fibrotic liver and activated HSCs. Fish oil administration to the model mouse attenuates CCl4-induced liver fibrosis. Further study revealed that ω-3 PUFAs down-regulate the expression of pro-fibrogenic genes in activated HSCs and fibrotic liver, and the down-regulation is mediated via YAP, thus identifying YAP as a target of ω-3 PUFAs. Moreover, ω-3 PUFAs promote YAP/TAZ degradation in a proteasome-dependent manner. Our data have identified a mechanism of ω-3 PUFAs in ameliorating liver fibrosis.

Highlights

Elevated levels of the transcriptional regulators Yes-associated protein (YAP) and transcriptional coactivators with PDZ-binding motif (TAZ), key effectors of the Hippo pathway, are associated with a broad range of aggressive cancers including hepatocellular carcinoma[15,16,17]
It has been reported that YAP/TAZ functions as a regulator of microprocessor activity and regulates biogenesis of miRNA28–30, some of which play an important role in liver fibrosis
The hydroxyproline content, a modified amino acid uniquely found in a high percentage in collagen, showed an approximate 30% reduction in fish oil/CCl4 group compared with CCl4 group (Fig. 1e), suggesting that fish oil could ameliorate the degree of liver fibrosis

Summary

Introduction

Elevated levels of the transcriptional regulators Yes-associated protein (YAP) and transcriptional coactivators with PDZ-binding motif (TAZ), key effectors of the Hippo pathway, are associated with a broad range of aggressive cancers including hepatocellular carcinoma[15,16,17]. Recent study has shown that YAP drives the earliest changes in gene expression during hepatic stellate cell activation[31]. Elevated YAP/TAZ expression correlates with bile duct proliferation and fibrosis[15,32,33]. Connecting these previously reported phenomena, we focused on the transcriptional effectors YAP/ TAZ as a potential regulator of liver fibrosis. We demonstrate for the first time that ω-3 PUFAs attenuate CCl4-induced liver fibrosis in vivo and inhibit hepatic stellate cell proliferation and activation. Ω-3 PUFAs inhibit hepatic stellate cell lines proliferation and activation by promoting YAP/TAZ degradation

Methods

Results

Conclusion